JAK-Inhibitors for the Treatment of Rheumatoid Arthritis: a Focus on the Present and an Outlook on the Future

biomolecules Review JAK-Inhibitors for the Treatment of Rheumatoid Arthritis: A Focus on the Present and an Outlook on the Future 1, 2, , 3 1,4 Jacopo Angelini y , Rossella Talotta * y , Rossana Roncato , Giulia Fornasier , Giorgia Barbiero 1, Lisa Dal Cin 1, Serena Brancati 1 and Francesco Scaglione 5 1 Postgraduate School of Clinical Pharmacology and Toxicology, University of Milan, 20133 Milan, Italy; [email protected] (J.A.); [email protected] (G.F.); [email protected] (G.B.); [email protected] (L.D.C.); [email protected] (S.B.) 2 Department of Clinical and Experimental Medicine, Rheumatology Unit, AOU “Gaetano Martino”, University of Messina, 98100 Messina, Italy 3 Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Pordenone, 33081 Aviano, Italy; [email protected] 4 Pharmacy Unit, IRCCS-Burlo Garofolo di Trieste, 34137 Trieste, Italy 5 Head of Clinical Pharmacology and Toxicology Unit, Grande Ospedale Metropolitano Niguarda, Department of Oncology and Onco-Hematology, Director of Postgraduate School of Clinical Pharmacology and Toxicology, University of Milan, 20162 Milan, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-090-2111; Fax: +39-090-293-5162 Co-first authors. y Received: 16 May 2020; Accepted: 1 July 2020; Published: 5 July 2020 Abstract: Janus kinase inhibitors (JAKi) belong to a new class of oral targeted disease-modifying drugs which have recently revolutionized the therapeutic panorama of rheumatoid arthritis (RA) and other immune-mediated diseases, placing alongside or even replacing conventional and biological drugs. JAKi are characterized by a novel mechanism of action, consisting of the intracellular interruption of the JAK-STAT pathway crucially involved in the immune response. The aim of this narrative review is to globally report the most relevant pharmacological features and clinical outcomes of the developed and incoming JAKi for RA, based on the available preclinical and clinical evidence. A total of 219 papers, including narrative and systematic reviews, randomized controlled trials (RCTs), observational studies, case reports, guidelines, and drug factsheets, were selected. The efficacy and safety profile of both the first generation JAKi (baricitinib and tofacitinib) and the second generation JAKi (upadacitinib, filgotinib, peficitinib, decernotinib and itacitinib) were compared and discussed. Results from RCTs and real-life data are encouraging and outline a rapid onset of the pharmacologic effects, which are maintained during the time. Their efficacy and safety profile are comparable or superior to those of biologic agents and JAKi proved to be efficacious when given as monotherapy. Finally, the manufacturing of JAKi is relatively easier and cheaper than that of biologics, thus increasing the number of compounds being formulated and tested for clinical use. Keywords: Janus kinases; Janus kinase-inhibitors; rheumatoid arthritis; small molecules 1. Introduction Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting approximately 0.5–1% of the worldwide population. RA prevalence is higher in women aged between 35 and 50 years than in age-matched men, though this difference is less evident among elderly patients [1,2]. Biomolecules 2020, 10, 1002; doi:10.3390/biom10071002 www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, 1002 2 of 40 RA is characterized by a chronic synovitis that symmetrically develops in small joints of hands and feet, but any synovial joint can actually be involved [3]. Articular manifestations include swelling, tenderness, warmth, and decreased range of motion. Over time, persistent inflammation leads to the destruction of joints and tendons, and, eventually, to deformities and ankylosis. In some cases, RA can have an extra-articular presentation, and inflammation may involve the skin, heart, lungs, and eyes [4,5]. Generalized malaise and fatigue, pleural involvement, vasculitis, pericarditis, myocardial infarction, rheumatoid nodules, nerve entrapment syndromes, and keratoconjunctivitis sicca are the most common extra-articular manifestations [6]. The etiology of RA is multifactorial, and the initial cause is unknown. It is assumed that in a genetically predisposed individual, an environmental agent, like infections or dysbiosis, can trigger an aberrant immune response against self-antigens placed in the articular sites [7,8]. Genetic predisposition is mirrored by the high concordance rates in twins, and several cases have been shown to occur in the same family [9]. More than one hundred genetic loci have been associated with RA risk [10], most of which preside over the control of the immune response [11,12]. Among them, polymorphic variants of the human leukocyte antigen (HLA) genes, coding for molecules involved in the antigen presentation process, have been associated to a more aggressive course of the disease or higher mortality rates [10,13]. Smoking, traumatic events, a low socioeconomic status, educational attainment, and periodontal disease are instead considered environmental risk factors for RA [14,15]. RA may be triggered by gut and oral dysbiosis or by infections sustained by Proteus mirabilis, Escherichia coli, or the Epstein–Barr virus [16,17]. Epigenetics may play an additional role in RA pathogenesis, being in turn influenced by environmental stimuli [18]. Histone deacetylation, DNA methylation, and microRNA production may affect the transcription of genes involved in inflammation, and are associated with disease risk and activity and response to treatment [19]. RA inflammation is due to the clonal expansion of autoreactive T cells, such as T helper (Th)17 lymphocytes and B lymphocytes at the detriment of T regulatory(reg) lymphocytes [20,21]. B lymphocytes mature to the final stage of plasma cells producing autoantibodies, including anti-citrullinated peptide antibodies (ACPAs) and rheumatoid factor (RF) that represent the serologic hallmark of the disease [21]. Autoreactive cells are recruited in the synovial membrane, where resident fibroblast-like and macrophage-like synoviocytes further contribute to the amplification of the inflammatory cascade through the release of several pro-inflammatory cytokines [7], like interleukin (IL)-1 and tumor necrosis factor-alpha (TNF-α), IL-6, and IL-8 [22]. Additionally, Th17 lymphocytes secrete IL-17 that is crucially involved in bone resorption [20]. Persistent inflammation results in profound changes of the joint anatomy and physiology, progressing from synovial hyperplasia and endothelial cell activation in the early phase to cartilage destruction and bone erosion in the late phase [23]. The recent 2020 European League Against Rheumatism (EULAR) and the 2015 American College of Rheumatology (ACR) guidelines recommended to start treating RA patients as early as possible owing to the debilitating course of the disease, and subjects should be tightly monitored as therapy should be adjusted according to disease activity [24,25]. The treatment of RA relies on the use of drugs counteracting the aberrant activation of the immune system and includes anti-inflammatory and analgesic drugs, glucocorticoids, disease-modifying anti-rheumatic drugs (DMARDs), immunosuppressive agents, and biologics. The DMARD methotrexate (MTX), and to a lesser extent, leflunomide and sulfasalazine, have been considered as an anchor therapy in RA. Accordingly, their use, as mono- or combo-therapy, is recommended in the early phase of the disease, as well as to treat the milder forms of RA in the long term. Glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) are, instead, indicated for the acute management of RA flares, while the chronic use of these drugs is discouraged. Conventional (c)DMARDs, glucocorticoids, and NSAIDs are characterized by a low target specificity and may unselectively hamper physiological Biomolecules 2020, 10, 1002 3 of 40 pathways other than the immune response, exposing patients to a not negligible risk of adverse events, like infections or gastrointestinal, cardiovascular, and hematologic disorders [26–28]. Since their advent in late 1990s [29], biological drugs consisting of monoclonal antibodies or fusion receptors targeting specific molecular or cellular pathways, notably improved the clinical course of RA, allowing the achievement of low disease activity or even remission in a high percentage of cases [30,31]. Additionally, in the last years, the formulation of oral compounds, known as small molecules, able to block some crucial steps of the inflammatory cascade, has further enriched RA therapeutic armamentarium. According to current therapeutic guidelines [24,25], biologic drugs and synthetic small molecules should be prescribed in the case of severe and refractory RA, but these medications may also be considered as the first therapy when poor prognostic factors are present [24]. Among synthetic small molecules, the Janus kinase inhibitors (JAKi) represent a new class of oral drugs counteracting the activation of JAKs, which are cytosolic enzymes presiding over many biologic functions, including the activation of the inflammatory cascade in immune cells [32]. Due to their central role in the immune response and their association with several cytokine receptors, the inhibition of JAKs appeared to be a promising strategy in autoimmune diseases. To date, some oral JAKi (tofacitinib, baricitinib, upadacitinib, peficitinib)

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